3-alkyl-5-fluoroindole derivatives as myeloperoxidase inhibitors

Abstract

The invention relates to a compound of formula (Ia) wherein n is an integer between 2 and 10, R 1 and R 2 independently represent a substituent selected from the group consisting of hydrogen, C 1 -C 10 alkyl, C 3 -C 10 cycloalkyl and aminoalkyl, or R 1 and R 2 are taken together with the nitrogen atom to which they are attached to form a four to ten-membered heterocycle, R 5 represents independently in each of the n units a substituent selected from the group consisting of hydrogen, C 1 -C 10 alkyl, halogen, alkoxy, aminoalkyl and alkylamino; or a pharmaceutically acceptable salt thereof, with the proviso that the 5-fluorotryptamine is excluded, for the treatment or the prophylaxis of neuroinflammatory diseases or disorders. The invention also relates to a pharmaceutical composition, a method for inhibiting myeloperoxidase enzyme activity, to a method for inhibiting Low density lipoproteins oxidation.

1 . Compounds of formula (Ia) 
       
         
           
           
               
               
           
         
         wherein 
         n is an integer between 2 and 10, 
         R 1  and R 2  independently represent a substituent selected from the group consisting of hydrogen, C 1 -C 10  alkyl, C 3 -C 10  cycloalkyl and aminoalkyl, or R 1  and 
         R 2  are taken together with the nitrogen atom to which they are attached to form a four to ten-membered heterocycle, 
         R 5  represents independently in each of the n units a substituent selected from the group consisting of hydrogen, C 1 -C 10  alkyl, halogen, alkoxy, aminoalkyl and alkylamino, 
       
       or pharmaceutically acceptable salts thereof, with the proviso that 5-fluorotryptamine is excluded, for the treatment or the prophylaxis of neuroinflammatory diseases or disorders. 
     
     
         2 . Compounds according to  claim 1 , wherein n is an integer between 2 and 6. 
     
     
         3 . Compounds according to  claim 1 , wherein R 5  represents independently in each of the n units a substituent selected from the group consisting of hydrogen and C 1 -C 6  alkyl ; R 1  and R 2  independently represent a substituent selected from the group consisting of hydrogen and C 1 -C 6  alkyl, or R 1  and R 2  are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, azepane and azocane. 
     
     
         4 . Compounds according to  claim 1 , wherein R 5  represents independently in each of the n units a substituent selected from the group consisting of hydrogen and C 1 -C 2  alkyl ; R 1  and R 2  independently represent a substituent selected from the group consisting of hydrogen and C 1 -C 2  alkyl, or R 1  and R 2  are taken together with the nitrogen atom to which they are attached to form a heterocycle selected from the group consisting of pyrrolidine and piperazine. 
     
     
         5 . Compounds according to of  claim 1 , wherein said compounds are selected from the group consisting of 3-(3-Aminopropyl)-5-fluoro-[1H]-indole, (3-(4-Aminobutyl)-5-fluoro-[1H]-indole, (5-Fluoro-3-[2-(1-pyrrolidinyl)ethyl]-[1H]-indole, (N,N-Dimethyl-3-(2-aminoethyl)-5-fluoro-[1H]-indole and 3-(5-aminopentyl)-5-fluoro-1H-indole oxalate, or a pharmaceutically acceptable salt thereof. 
     
     
         6 . Compounds according to  claim 1 , wherein said compound has an IC 50  value equal or less than 0.2 μM against myeloperoxidase enzyme. 
     
     
         7 . Compounds according to  claim 1 , where the neuroinflammatory diseases or disorders are selected from the group consisting of multiple sclerosis, atherosclerosis, Alzheimer's disease, chronic pulmonar disease, chronic inflammatory syndromes linked to joints and Parkinson's disease. 
     
     
         8 . Pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (Ia) according to  claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 
     
     
         9 . A method for the treatment or prophylaxis of neuroinflammatory diseases or disorders comprising administering a pharmaceutical composition according to  claim 8 . 
     
     
         10 . The method according to  claim 9  where said neuroinflammatory diseases or disorders are selected from the group consisting of multiple sclerosis, atherosclerosis, Alzheimer's disease, chronic pulmonar disease, chronic inflammatory syndromes linked to joints and Parkinson's disease. 
     
     
         11 . Method for inhibiting myeloperoxidase enzyme activity comprising the step of adding a compound according to any one of  claim 1  to a medium containing said enzyme, said compound being added in a concentration effective to inhibit the activity of said enzyme. 
     
     
         12 . (canceled) 
     
     
         13 . Method for the treatment of atherosclerosis comprising the step of administering a therapeutically effective amount of a compound of formula (Ia) according to  claim 1  or a therapeutically effective amount of a pharmaceutical composition according to  claim 8 , to a patient in need thereof. 
     
     
         14 . Method for inhibiting low density lipoproteins (LDL) oxidation comprising the step of contacting a compound of formula (Ia) according to  claim 1  in a medium containing said low density lipoproteins and myeloperoxidase enzyme. 
     
     
         15 . (canceled)